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Remifentanil-induced hyperalgesia (RIH) is a part of a general opioid-induced hyperalgesia (OIH) syndrome, seemingly resulting from abrupt cessation of continuous remifentanil infusion at rates equal or exceeding 0.3 mcg/kg/min. The intricate mechanisms of its development are still not completely understood. However, hyperactivation of the N -methyl d -aspartate receptor system, descending spinal facilitation and increased concentration of dynorphin (a κ-opioid ligand) are commonly proposed as possible mechanisms. Several ways of prevention and management have been suggested, such as slow withdrawal of remifentanil infusion, the addition of propofol, pretreatment with or concomitant administration of ketamine, buprenorphine, cyclooxygenase-2 inhibitors (NSAIDs), methadone, dexmedetomidine. In clinical and animal studies, these strategies exhibited varying success, and many are still being investigated., (Copyright © 2024 Wolters Kluwer Health, Inc. All rights reserved.)

Abstract: Animal and human studies have shown that exercise prior to nerve injury prevents later chronic pain, but the mechanisms of such preconditioning remain elusive. Given that exercise acutely increases the formation of free radicals, triggering antioxidant compensation, we hypothesized that voluntary running preconditioning would attenuate neuropathic pain by supporting redox homeostasis after sciatic nerve injury in male and female rats. We show that 6 weeks of voluntary wheel running suppresses neuropathic pain development induced by chronic constriction injury across both sexes. This attenuation was associated with reduced nitrotyrosine immunoreactivity-a marker for peroxynitrite-at the sciatic nerve injury site. Our data suggest that prior voluntary wheel running does not reduce the production of peroxynitrite precursors, as expression levels of inducible nitric oxide synthase and NADPH oxidase 2 were unchanged. Instead, voluntary wheel running increased superoxide scavenging by elevating expression of superoxide dismutases 1 and 2. Prevention of neuropathic pain was further associated with the activation of the master transcriptional regulator of the antioxidant response, nuclear factor E2-related factor 2 (Nrf2). Six weeks of prior voluntary wheel running increased Nrf2 nuclear translocation at the sciatic nerve injury site; in contrast, 3 weeks of prior wheel running, which failed to prevent neuropathic pain, had no effect on Nrf2 nuclear translocation. The protective effects of prior voluntary wheel running were mediated by Nrf2, as suppression was abolished across both sexes when Nrf2 activation was blocked during the 6-week running phase. This study provides insight into the mechanisms by which physical activity may prevent neuropathic pain. Preconditioning by voluntary wheel running, terminated prior to nerve injury, suppresses later neuropathic pain in both sexes, and it is modulated through the activation of Nrf2-antioxidant signaling., (Copyright © 2022 International Association for the Study of Pain.)

Study Design: Prospective longitudinal experimental study., Objective: We evaluate the effect of dapsone on tactile allodynia and mechanical hyperalgesia and to determine its anti-oxidant effect in a spinal cord injury (SC) model in rats., Summary of Background Data: Neuropathic pain (NP) as result of traumatic spinal cord injury is a deleterious medical condition with temporal or permanent time-course. Painful stimuli trigger a cascade of events that activate the N-methyl-D-aspartate (NMDA) receptor, inducing an increase in oxidative stress. Since there is no effective treatment for this condition, dapsone (4,4'diaminodiphenylsulfone) is proposed as potential treatment for NP. Its anti-oxidant, neuroprotective, and anti-inflammatory properties have been documented, however, there is no evidence regarding its use for treatment of NP induced by SCI., Methods: In this study, we evaluated the anti-allodynic and anti-hyperalgesic effect of dapsone as preventive or acute treatment after NP was already established. Furthermore, participation of oxidative stress was evaluated by measuring lipid peroxidation (LP) and glutathione concentration (GSH) in rats with SCI., Results: Acute treatment with dapsone (3.1-25 mg/kg, i.p.) decreased nociceptive behaviors in a dose-dependent manner, decreased LP, and increased GSH in the injured tissue 15 days after the injury was produced. On the other hand, preventive treatment (3 h post-injury, once daily for 3 days) with dapsone (3.1-25 mg/kg, i.p.) yielded similar results., Conclusion: The findings suggest that the anti-nociceptive effect of dapsone is regulated through the decrease of oxidative stress and the excitotoxicity is associated with the activation of NMDA receptors.Level of Evidence: N/A., (Copyright © 2021 Wolters Kluwer Health, Inc. All rights reserved.)

Background: Remifentanil can induce postinfusion cold hyperalgesia. N-methyl-d-aspartate receptor (NMDAR) activation and upregulation of transient receptor potential melastatin 8 (TRPM8) membrane trafficking in dorsal root ganglion (DRG) are critical to cold hyperalgesia derived from neuropathic pain, and TRPM8 activation causes NMDAR-dependent cold response. Contribution of P2Y1 purinergic receptor (P2Y1R) activation in DRG to cold pain hypersensitivity and NMDAR activation induced by P2Y1R upregulation in neurons are also unraveled. This study explores whether P2Y1R contributes to remifentanil-induced cold hyperalgesia via TRPM8-dependent regulation of NMDAR phosphorylation in DRG., Methods: Rats with remifentanil-induced cold hyperalgesia were injected with TRPM8 antagonist or P2Y1R antagonist at 10 minutes before remifentanil infusion. Cold hyperalgesia (paw lift number and withdrawal duration on cold plate) was measured at -24, 2, 6, 24, and 48 hours following remifentanil infusion. After the last behavioral test, P2Y1R expression, TRPM8 expression and membrane trafficking, and NMDAR subunit (NR1 and NR2B) expression and phosphorylation in DRG were detected by western blot, and colocalization of P2Y1R with TRPM8 was determined by double-labeling immunofluorescence. Two-way repeated measures analysis of variance (ANOVA) or 2 × 2 factorial design ANOVA with repeated measures was used to analyze behavioral data of cold hyperalgesia. One-way ANOVA followed by Bonferroni post hoc comparisons was used to analyze the data in western blot and immunofluorescence., Results: Remifentanil infusion (1 μg·kg-1·min-1 for 60 minutes) induced cold hyperalgesia (hyperalgesia versus control, paw lift number and withdrawal duration on cold plate at 2-48 hours, P < .0001) with upregulated NR1 (hyperalgesia versus naive, 48 hours, mean ± standard deviation [SD], 114.00% ± 12.48% vs 41.75% ± 5.20%, P < .005) and NR2B subunits expression (104.13% ± 8.37% vs 24.63% ± 4.87%, P < .005), NR1 phosphorylation at Ser896 (91.88% ± 7.08% vs 52.00% ± 7.31%, P < .005) and NR2B phosphorylation at Tyr1472 (115.75% ± 8.68% vs 59.75% ± 7.78%, P < .005), TRPM8 expression (115.38% ± 9.27% vs 40.50% ± 4.07%, P < .005) and membrane trafficking (112.88% ± 5.62% vs 48.88% ± 6.49%, P < .005), and P2Y1R expression (128.25% ± 14.86% vs 45.13% ± 7.97%, P < .005) in DRG. Both TRPM8 and P2Y1R antagonists attenuated remifentanil-induced cold hyperalgesia and downregulated increased NR1 and NR2B expression and phosphorylation induced by remifentanil (remifentanil + RQ-00203078 versus remifentanil + saline, NR1 phosphorylation, 69.38% ± 3.66% vs 92.13% ± 4.85%; NR2B phosphorylation, 72.25% ± 6.43% vs 111.75% ± 11.00%, P < .0001). NMDAR activation abolished inhibition of TRPM8 and P2Y1R antagonists on remifentanil-induced cold hyperalgesia. P2Y1R antagonist inhibited remifentanil-evoked elevations in TRPM8 expression and membrane trafficking and P2Y1R-TRPM8 coexpression (remifentanil + 2'-deoxy-N6-methyl adenosine 3',5'-diphosphate [MRS2179] versus remifentanil + saline, coexpression, 8.33% ± 1.33% vs 22.19% ± 2.15%, P < .0001)., Conclusions: Attenuation of remifentanil-induced cold hyperalgesia by P2Y1R inhibition is attributed to downregulations in NMDAR expression and phosphorylation via diminishing TRPM8 expression and membrane trafficking in DRG., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2021 International Anesthesia Research Society.)

Background: Consecutive exposure to high-dose remifentanil during anesthesia may induce remifentanil-induced postinfusion hyperalgesia (RPH). Dexmedetomidine, a highly selective α2-adrenergic receptor agonist, may have synergistic effects with opioids and aid in perioperative pain management. In this study, we hypothesized that an intraoperative bolus dose of intravenous dexmedetomidine could alleviate RPH in patients undergoing thyroidectomy under general anesthesia., Methods: Ninety patients undergoing thyroidectomy were randomly assigned to 1 of 3 groups: placebo, normal saline (group P); low-dose dexmedetomidine 0.2 μg·kg-1 (group LD); or high-dose dexmedetomidine 0.5 μg·kg-1 (group HD). Remifentanil was infused at a rate of 0.30 μg·kg-1·minute-1. Mechanical pain thresholds were measured using an Electronic von Frey device preoperatively and at 30 minutes, 6 hours, 24 hours, and 48 hours after surgery and were analyzed with 2-way repeated-measures analysis of variance (ANOVA) followed by Bonferroni post hoc comparison. We also recorded postoperative pain scores, the incidence of receiving rescue analgesics, and side effects up to 48 hours after surgery., Results: The mechanical pain thresholds around the skin incision were significantly higher in group LD compared to group P 30 minutes and 6 hours after surgery (mean ± standard deviation: [65.0 ± 25.2] vs [49.6 ± 24.4] g, mean difference [95% confidence interval]: 15.4 [0.3-30.5] g, P = .045 at 30 minutes; [65.9 ± 24.5] vs [49.3 ± 26.1] g, 16.6 [1.1-32.1] g, P = .032 at 6 hours). The pain thresholds around the skin incision were significantly higher in group HD compared to group P 30 minutes and 6 hours after surgery ([67.8 ± 21.7] vs [49.6 ± 24.4] g, 18.2 [3.1-33.3] g, P = .013 at 30 minutes; [68.3 ± 22.5] vs [49.3 ± 26.1] g, 19.0 [3.5-34.5] g, P = .011 at 6 hours). The incidence of hyperalgesia around the skin incision was lower in group HD than in group P 30 minutes and 6 hours after surgery (4 [13%] vs 14 [48%], P = .012 at 30 minutes, 4 [13%] vs 12 [41%], P = .045 at 6 hours), although no significant difference was observed between group LD and group P. Postoperative pain scores, the incidence of rescue analgesic demand, and postoperative side effects were not significantly different between the groups., Conclusions: An intraoperative intravenous bolus dose of dexmedetomidine 0.5 μg·kg-1 alleviates remifentanil-induced hyperalgesia in patients undergoing thyroidectomy without a significant difference in side effects., Competing Interests: The authors declare no conflicts of interest., (Copyright © 2020 International Anesthesia Research Society.)

Background: Ketamine, a commonly used nonbarbiturate anesthetic drug, possesses antidepressant properties at subanesthetic doses; however, the underlying mechanisms remain unclear., Materials and Methods: The analgesic and antidepressant effects of ketamine were explored using a complete Freund adjuvant (CFA)-induced peripheral inflammatory pain model in vivo. Mice were first divided into sham or CFA injection group randomly, and were observed for mechanical hyperalgesia, depression-like behavior, and mRNA expression of caveolin-1. Then ketamine was administered in CFA-treated mice at day 7., Results: The behavioral testing results revealed mechanical hyperalgesia and depression in mice from days 7 to 21 after CFA injection. Ketamine reversed depression-like behaviors induced by CFA injection. It also restored the brain-regional expression levels of caveolin-1 in CFA-treated mice. In addition, caveolin-1 mRNA and protein expression were increased in the prefrontal cortex and nucleus accumbens of CFA-treated mice. However, ketamine reversed the increase in caveolin-1 expression in the ipsilateral and contralateral prefrontal cortex and nucleus accumbens, supporting the distinct roles of specific brain regions in the regulation of pain and depression-like behaviors., Conclusions: In CFA-treated mice that exhibited pain behavior and depression-like behavior, ketamine reversed depression-like behavior. The prefrontal cortex and nucleus accumbens are the important brain regions in this regulation network. Despite these findings, other molecules and their mechanisms in the signal pathway, as well as other regions of the brain in the pain matrix, require further exploration.

Background: Patients undergoing cancer treatment often experience chemotherapy-induced neuropathic pain at their extremities, for which there is no U.S. Food and Drug Administration-approved drug. The authors hypothesized that local sympathetic blockade, which is used in the clinic to treat various pain conditions, can also be effective to treat chemotherapy-induced neuropathic pain., Methods: A local sympathectomy (i.e., cutting the ipsilateral gray rami entering the spinal nerves near the L3 and L4 dorsal root ganglia) was performed in mice receiving intraperitoneal injections every other day of the chemotherapeutic drug paclitaxel. Sympathectomy effects were then assessed in chemotherapy-induced pain-like behaviors (i.e., mechanical and cold allodynia) and neuroimmune and electrophysiologic responses., Results: Local microsympathectomy produced a fast recovery from mechanical allodynia (mean ± SD: sympathectomy vs. sham at day 5, 1.07 ± 0.34 g vs. 0.51 ± 0.17g, n = 5, P = 0.030 in male mice, and 1.08 ± 0.28 g vs. 0.62 ± 0.16 g, n = 5, P = 0.036 in female mice) and prevented the development of cold allodynia in both male and female mice after paclitaxel. Mechanistically, microsympathectomy induced transcriptional increases in dorsal root ganglia of macrophage markers and anti-inflammatory cytokines, such as the transforming growth factor-β. Accordingly, depletion of monocytes/macrophages and blockade of transforming growth factor-β signaling reversed the relief of mechanical allodynia by microsympathectomy. In particular, exogenous transforming growth factor-β was sufficient to relieve mechanical allodynia after paclitaxel (transforming growth factor-β 100 ng/site vs. vehicle at 3 h, 1.21 ± 0.34g vs. 0.53 ± 0.14 g, n = 5, P = 0.001 in male mice), and transforming growth factor-β signaling regulated neuronal activity in dorsal root ganglia., Conclusions: Local sympathetic nerves control the progression of immune responses in dorsal root ganglia and pain-like behaviors in mice after paclitaxel, raising the possibility that clinical strategies already in use for local sympathetic blockade may also offer an effective treatment for patients experiencing chemotherapy-induced neuropathic pain.

About half of patients with spinal cord injury (SCI) develop debilitating central neuropathic pain (CNP), with no effective treatments. Thus, effective, safe, and novel therapies are needed urgently. Previously, docosahexaenoic acid (DHA) was reported to confer neuroprotection in preclinical SCI models. However, its therapeutic potential on SCI-CNP remains to be elucidated. Here, we demonstrated for the first time that intravenous DHA administrations with 3-day intervals (250 nmol/kg; starting 30 minutes after injury and maintained for 6 weeks) effectively prevented SCI-CNP development in a clinically relevant rat contusion model. SCI-CNP was assessed by a novel sensory profiling approach combining evoked pain measures and pain-related ethologically relevant rodent behaviours (burrowing, thigmotaxis, and place/escape avoidance) to mimic those for measuring human (sensory, affective, cognitive, and spontaneous) pain. Strikingly, already established SCI-CNP could be abolished partially by similar DHA administrations, starting from the beginning of week 4 after injury and maintained for 4 weeks. At spinal (epicenter and L5 dorsal horns) and supraspinal (anterior cingulate cortex) levels, both treatment regimens potently suppressed microglial and astrocyte activation, which underpins SCI-CNP pathogenesis. Spinal microgliosis, a known hallmark associated with neuropathic pain behaviours, was reduced by DHA treatments. Finally, we revealed novel potential roles of peroxisome proliferator-activated and retinoid X receptors and docosahexaenoyl ethanolamide (DHA's metabolite) in mediating DHA's effects on microglial activation. Our findings, coupled with the excellent long-term clinical safety of DHA even in surgical and critically ill patients, suggest that systemic DHA treatment is a translatable, effective, safe, and novel approach for preventing and managing SCI-CNP.

Background: Recently, we demonstrated that the antipsychotic dopaminergic and serotoninergic agonist aripiprazole induced peripheral antinociception. However, the mechanism underlying this effect has not been fully established. Here, our aim was to identify possible relationships between this action of aripiprazole and the endocannabinoid system., Methods: All drugs were given locally into the right hind paw of male Swiss mice weighing 30-35 g in a volume of 20 µL. The hyperalgesia was induced by intraplantar injection of prostaglandin E2 (2 μg). Aripiprazole was injected 10 minutes before the measurement, and an irreversible inhibitor of anandamide hydrolase (MAFP), an inhibitor for monoacylglycerol lipase (JZL184), and an anandamide reuptake inhibitor (VDM11) were given 10 minutes before the aripiprazole. Nociceptive thresholds were measured using an algesimetric apparatus in the third hour after prostaglandin E2 injection. Data were analyzed by ANOVA and Bonferroni tests., Results: The antinociceptive effect induced by aripiprazole (100 μg) was blocked by cannabinoid 1 or 2 receptor antagonists AM251 (40 μg [P < .01], 80 μg [P < .0001], and 160 μg [P < .0001]) and AM630 (100 μg [P < .0001], 200 μg [P < .0001], and 400 μg [P < .0001]), respectively. The peripheral antinociception induced by aripiprazole (25 μg) was enhanced by administration of the inhibitor of fatty acid amide hydrolase (MAFP, 0.5 μg [P < .0001]) or monoacylglycerol lipase (JZL184, 4 μg [P < .0001]). Moreover, a similar enhancement was observed with the anandamide reuptake inhibitor (VDM11, 2.5 μg [P < .0001])., Conclusions: These results provide evidence for the involvement of the endocannabinoid system in peripheral antinociception induced by aripiprazole treatment.

Background: Diabetes mellitus affects 9.3% of the US population and increases risks of surgery and complications. Diabetic neuropathic pain (DNP), one of the main consequences of diabetes mellitus, is extremely difficult to treat. Current medications yield limited benefits and/or have severe adverse effects. Therefore, new, effective treatment is needed., Methods: Streptozotocin at 55 mg/kg was injected intraperitoneally in rats to induce diabetes mellitus. Diabetic rats exhibiting neuropathic pain underwent intrathecal injection of purified agrin proteins at various doses and were then tested for tactile allodynia to evaluate whether DNP was inhibited. The agrin effects were also analyzed with patch-clamp recording on spinal cord slices., Results: Fifty-kilo Dalton agrin (Agr50) at 0.2 and 2 ng suppressed DNP when given intrathecally, while 25- and 75-kDa agrin (Agr25, Agr75) had little effect. The suppressive effect of Agr50 lasted 4 hours after a single bolus injection. The difference in effects of Agr50 on mean withdrawal threshold (4.6 ± 2.2 g before treatment to 26 ± 0 g after treatment) compared with that of Agr25 (4.9 ± 2.0 g to 4.9 ± 2.0 g) and Agr75 (5.3 ± 2.3 g to 9.2 ± 2.5 g) was highly significant (P < .01). On spinal cord slices, Agr50 increased spontaneous GABAergic current activities, suggesting increased spontaneous inhibitory postsynaptic currents and action potential firing rate from GABA neurons, whereas Agr25 and Agr75 had no such effect., Conclusions: Agr50 had a potent suppressive effect on DNP and increased spontaneous inhibitory postsynaptic currents and action potential firing rate from GABA neurons. Therefore, Agr50 may provide a potential therapy for DNP.

What We Already Know About This Topic: WHAT THIS ARTICLE TELLS US THAT IS NEW: BACKGROUND:: Recovery from pain after surgery is faster after cesarean delivery than after other abdominal procedures. The authors hypothesized that recovery in rats after surgery could be reversed by antagonism of spinal oxytocin or vasopressin receptors, that there may be a sex difference, and that spinal oxytocin innervation could change after surgery., Methods: Male and female rats underwent partial spinal nerve ligation surgery. Effects of nonselective and selective oxytocin and vasopressin 1A receptor antagonists on mechanical hypersensitivity during partial recovery were assessed (n = 8 to 14/group). Oxytocin immunoreactivity in the dorsal horn of the spinal cord (n = 7 to 8/group) and messenger RNA (mRNA) expression for oxytocin-binding receptors in dorsal root ganglia and spinal cord (n = 8/group) were measured., Results: Intrathecal injection of oxytocin and vasopressin receptor antagonists were similarly effective at reducing withdrawal threshold (in all experiments from 22 [19, 26] median [first quartile, third quartile]) g to 8.3 [6.4, 12] g after injection) in both sexes, while having no or minimal effects in animals without surgery. Oxytocin fiber immunoreactivity was 3- to 5-fold greater in lumbar than other regions of the spinal cord and was increased more than 2-fold in lumbar cord ipsilateral to surgery. Injury was also associated with a 6.5-fold increase in oxytocin receptor and a 2-fold increase in vasopressin 1A receptor messenger RNA expression in the L4 dorsal root ganglion ipsilateral to surgery., Conclusions: These findings suggest that the capacity for oxytocin signaling in the spinal cord increases after surgery and that spinal oxytocin signaling plays ongoing roles in both sexes in recovery from mechanical hypersensitivity after surgery with known nerve injury.

The development of chronic pain is considered a major complication after surgery. Basic science research in animal models helps us understand the transition from acute to chronic pain by identifying the numerous molecular and cellular changes that occur in the peripheral and central nervous systems. It is now well recognized that inflammation and nerve injury lead to long-term synaptic plasticity that amplifies and also maintains pain signaling, a phenomenon referred to as pain sensitization. In the context of surgery in humans, pain sensitization is both responsible for an increase in postoperative pain via the expression of wound hyperalgesia and considered a critical factor for the development of persistent postsurgical pain. Using specific drugs that block the processes of pain sensitization reduces postoperative pain and prevents the development of persistent postoperative pain. This narrative review of the literature describes clinical investigations evaluating different preventative pharmacologic strategies that are routinely used by anesthesiologists in their daily clinical practices for preventing persistent postoperative pain. Nevertheless, further efforts are needed in both basic and clinical science research to identify preclinical models and novel therapeutics targets. There remains a need for more patient numbers in clinical research, for more reliable data, and for the development of the safest and the most effective strategies to limit the incidence of persistent postoperative pain.

Background: Liver X receptors, including α and β isoforms, are ligand-activated transcription factors. Whether liver X receptor α plays a role in neuropathic pain is unknown., Methods: A spared nerve injury model was established in adult male rats and mice. Von Frey tests were performed to evaluate the neuropathic pain behavior; Western blot and immunohistochemistry were performed to understand the underlying mechanisms., Results: Intrathecal injection of a specific liver X receptor agonist T0901317 or GW3965 could either prevent the development of mechanical allodynia or alleviate the established mechanical allodynia, both in rats and wild-type mice. GW3965 could inhibit the activation of glial cells and the expression of tumor necrosis factor-α (mean ± SD: 196 ± 48 vs. 119 ± 57; n = 6; P < 0.01) and interleukin 1β (mean ± SD: 215 ± 69 vs. 158 ± 74; n = 6; P < 0.01) and increase the expression of interleukin 10 in the spinal dorsal horn. All of the above effects of GW3965 could be abolished by liver X receptor α mutation. Moreover, more glial cells were activated, and more interleukin 1β was released in the spinal dorsal horn in liver X receptor α knockout mice than in wild-type mice after spared nerve injury. Aminoglutethimide, a neurosteroid synthesis inhibitor, blocked the inhibitory effect of T0901317 on mechanical allodynia, on the activation of glial cells, and on the expression of cytokines., Conclusions: Activation of liver X receptor α inhibits mechanical allodynia by inhibiting the activation of glial cells and rebalancing cytokines in the spinal dorsal horn via neurosteroids.

Regular physical activity prevents the development of chronic muscle pain through the modulation of central mechanisms that involve rostral ventromedial medulla (RVM). We tested if pharmacological blockade or genetic deletion of mu-opioid receptors in physically active mice modulates excitatory and inhibitory systems in the RVM in an activity-induced hyperalgesia model. We examined response frequency to mechanical stimulation of the paw, muscle withdrawal thresholds, and expression of phosphorylation of the NR1 subunit of the N-methyl-D-aspartate receptor (p-NR1) and serotonin transporter (SERT) in the RVM. Mice that had performed 5 days of voluntary wheel running prior to the induction of the model were compared with sedentary mice. Sedentary mice showed significant increases in mechanical paw withdrawal frequency and a reduction in muscle withdrawal threshold; wheel running prevented the increase in paw withdrawal frequency. Naloxone-treated and MOR mice had increases in withdrawal frequency that were significantly greater than that in physically active control mice and similar to sedentary mice. Immunohistochemistry in the RVM showed increases in p-NR1 and SERT expression in sedentary mice 24 hours after the induction of the model. Wheel running prevented the increase in SERT, but not p-NR1. Physically active, naloxone-treated, and MOR mice showed significant increases in SERT immunoreactivity when compared with wild-type physically active control mice. Blockade of SERT in the RVM in sedentary mice reversed the activity-induced hyperalgesia of the paw and muscle. These results suggest that analgesia induced by 5 days of wheel running is mediated by mu-opioid receptors through the modulation of SERT, but not p-NR1, in RVM.

Purpose of Review: This article reviews the phenomenon of opioid-induced hyperalgesia (OIH) and its implications for clinical anesthesia. The goal of this review is to give an update on perioperative prevention and treatment strategies, based on findings in preclinical and clinical research., Recent Findings: Several systems have been suggested to be involved in the pathophysiology of OIH with a focus on the glutaminergic system. Very recently preclinical data revealed that peripheral μ-opioid receptors (MORs) are key players in the development of OIH and acute opioid tolerance (AOT). Peripheral MOR antagonists could, thus, become a new prevention/treatment option of OIH in the perioperative setting. Although the impact of OIH on postoperative pain seems to be moderate, recent evidence suggests that increased hyperalgesia following opioid treatment correlates with the risk of developing persistent pain after surgery. In clinical practice, distinction among OIH, AOT and acute opioid withdrawal remains difficult, especially because a specific quantitative sensory test to diagnose OIH has not been validated yet., Summary: Since the immediate postoperative period is not ideal to initiate long-term treatment for OIH, the best strategy is to prevent its occurrence. A multimodal approach, including choice of opioid, dose limitations and addition of nonopioid analgesics, is recommended.

Background: Reinnervation timing after nerve injury is critical for favorable axonal regeneration, remyelination, and clinical improvement. Considering bone marrow mononuclear cells (BMMC) are easily obtained and readily available for transplant, this work analyzed the effect of BMMC systemic administration on nerve repair and pain behavior., Methods: Adult rats with sciatic nerve crush were immediately and systemically injected BMMC through the caudal artery. Nontreated, sham and naïve rats were also included. Histological, immunohistochemical, biochemical, functional, and behavioral analyses were performed in nerves harvested from each group at different survival times., Results: Axons in BMMC-treated rats exhibited a more conserved morphological appearance than those in nontreated rats, as observed at different survival times both in semithin sections and ultrastructural analysis. BMMC-treated rats also showed a reduction in major myelin protein immunoreactive clusters 7 and 14 days postinjury, as compared with nontreated rats. Electrophysiological analysis showed BMMC treatment to slightly improve the amplitude of compound muscle action potential starting at 14 days postinjury. Finally, mechanical withdrawal threshold revealed a full preventive action against transient mechanical hypersensitivity in BMMC-treated rats., Conclusions: These data demonstrate the efficiency of BMMC, systemically and noninvasively transplanted, in correcting morphological, functional and behavioral alterations resulting from peripheral nerve injury.

Studies designed to assess persistent postoperative pain (PPP) incidence after hepatectomies are lacking. Our aim was to assess PPP incidence 6 months after hepatectomies with intravenous (IV) or epidural (EPI) analgesia containing ketamine.Prospective observational comparative study between 2 cohorts of patients submitted to hepatectomy. Patients received 1 of 2 analgesic regimes containing ketamine: EPI group or IV group. Visual analog scale (VAS), Neuropathic Pain Symptom Inventory (NPSI), Pain Catastrophizing Scale (PCS), and quantitative sensorial testing (QST: to determine area of hyperalgesia/allodynia) were assessed preoperatively and postoperatively at 2 h, 24 h, 7 days, 1 month, and 6 months. VAS ≥ 1 at 1 and 6 months was considered indicative of PPP and VAS > 3 was considered as not controlled pain. Side effects and complications were registered.Forty-four patients were included: 23 in EPI group and 21 in IV group. Patients in IV group were older and had more comorbidities. No patient presented VAS > 3 at 1 or 6 months. VAS ≥ 1 at 1 and 6 months was 36.4% and 22.7%, respectively. No differences in VAS, NPSI, or PCS were found between groups. Allodynia/hyperalgesia area did not differ between groups and was infrequent and slight. Pain pressure threshold in the wound vertical component was significantly higher in EPI group after 7 days. IV group showed more cognitive side effects.Incidence of PPP at 6 months after open hepatectomies with EPI or IV analgesia containing ketamine was lower than previously reported for other abdominal surgeries.Ketamine influence on low PPP incidence and hyperalgesia cannot be discarded.

Background: There is no widely recognized effective technique to optimally reduce pain scores and prevent persistent postoperative pain after nephrectomy. We compared continuous surgical site analgesia (CSSA), epidural analgesia (EA), and a control group (patient-controlled analgesic morphine) in patients undergoing open nephrectomy., Methods: Sixty consecutive patients were randomized to be part of EA, CSSA, or control groups postoperatively for 72 hours. All patients received patient-controlled analgesic morphine, if needed. Hyperalgesia was assessed on the first, second, and third postoperative days. Chronic pain characteristics and quality of life were analyzed at 1 and 3 months. The primary outcome was the pain score at 24 hours. Secondary outcomes were morphine consumption, postoperative rehabilitation, hyperalgesia, chronic pain incidence, and quality-of-life parameters., Results: At 24 hours, mean ± standard deviation pain values at rest (2.4 ± 1.7, 2.2 ± 1.2, and 4.2 ± 1.2, respectively, in EA, CSSA, and control groups, P <.001) and during coughing was lower in the EA and CSSA groups. Total morphine consumption was higher in the control group. Rehabilitation parameters improved sooner in the EA and CSSA groups. Median values of area of hyperalgesia differed at 48 hours between the EA group and the control group (36.4 cm) and (52 cm) (P = .01) and at 72 hours among the EA group, CSSA group, and the control group (40 cm, 39.5 cm, and 59 cm, respectively; P = .002). CSSA reduced the severity of pain and hyperalgesia at 1 month and optimized quality of life 3 months after surgery (role physical scores, P = .005)., Conclusions: CSSA and EA significantly improve postoperative analgesia, reduce postoperative morphine consumption, area of wound hyperalgesia, and accelerate patient rehabilitation after open nephrectomy. CSSA significantly reduces the severity of residual pain 1 month after surgery and optimizes quality-of-life parameters 3 months after surgery.

Background: The anterior cingulate cortex (ACC) is a brain region that has been critically implicated in the processing of pain perception and modulation. While much evidence has pointed to an increased activity of the ACC under chronic pain states, less is known about whether pain can be alleviated by inhibiting ACC neuronal activity., Methods: The authors used pharmacologic, chemogenetic, and optogenetic approaches in concert with viral tracing technique to address this issue in a mouse model of bone cancer-induced mechanical hypersensitivity by intratibia implantation of osteolytic fibrosarcoma cells., Results: Bilateral intra-ACC microinjections of γ-aminobutyric acid receptor type A receptor agonist muscimol decreased mechanical hypersensitivity in tumor-bearing mice (n =10). Using adenoviral-mediated expression of engineered Gi/o-coupled human M4 (hM4Di) receptors, we observed that activation of Gi/o-coupled human M4 receptors with clozapine-N-oxide reduced ACC neuronal activity and mechanical hypersensitivity in tumor-bearing mice (n = 11). In addition, unilateral optogenetic silencing of ACC excitatory neurons with halorhodopsin significantly decreased mechanical hypersensitivity in tumor-bearing mice (n = 4 to 9), and conversely, optogenetic activation of these neurons with channelrhodopsin-2 was sufficient to provoke mechanical hypersensitivity in sham-operated mice (n = 5 to 9). Furthermore, we found that excitatory neurons in the ACC send direct descending projections to the contralateral dorsal horn of the lumbar spinal cord via the dorsal corticospinal tract., Conclusions: The findings of this study indicate that enhanced neuronal activity in the ACC contributes to maintain bone cancer-induced mechanical hypersensitivity and suggest that the ACC may serve as a potential therapeutic target for treating bone cancer pain.

Background: Recent studies indicated the involvement of some chemokines in the development of diabetic neuropathy; however, participation of the chemokine-C-motif ligand (XCL) subfamily remains unknown. The goal of this study was to examine how microglial inhibition by minocycline hydrochloride (MC) influences chemokine-C-motif ligand 1 (XCL1)-chemokine-C-motif receptor 1 (XCR1)/G protein-coupled receptor 5 expression and the development of allodynia/hyperalgesia in streptozotocin-induced diabetic neuropathy., Methods: The studies were performed on streptozotocin (200 mg/kg, intraperitoneally)-induced mouse diabetic neuropathic pain model and primary glial cell cultures. The MC (30 mg/kg, intraperitoneally) was injected two times daily until day 21. XCL1 and its neutralizing antibody were injected intrathecally, and behavior was evaluated with von Frey and cold plate tests. Quantitative analysis of protein expression of glial markers, XCL1, and/or XCR1 was performed by Western blot and visualized by immunofluorescence., Results: MC treatment diminished allodynia (0.9 ± 0.1 g; n = 7 vs. 3.8 ± 0.7 g; n = 7) and hyperalgesia (6.5 ± 0.6 s; n = 7 vs. 16.5 ± 1 s; n = 7) in the streptozotocin-induced diabetes. Repeated MC administration prevented microglial activation and inhibited the up-regulation of the XCL1/XCR1 levels. XCL1 administration (10 to 500 ng/5 μl; n = 9) in naive mice enhanced nociceptive transmission, and injections of neutralizing XCL1 (4 to 8 μg/5 μl; n = 10) antibody into the mice with diabetic neuropathic pain diminished allodynia/hyperalgesia. Microglia activation evoked in primary microglial cell cultures resulted in enhanced XCL1 release and XCR1 expression. Additionally, double immunofluorescence indicated the widespread coexpression of XCR1-expressing cells with spinal neurons., Conclusions: In diabetic neuropathy, declining levels of XCL1 evoked by microglia inhibition result in the cause of analgesia. The putative mechanism corroborating this finding can be related to lower spinal expression of XCR1 together with the lack of stimulation of these XCR1 receptors, which are localized on neurons.

Chronic pain is categorized as inflammatory and neuropathic, and there are common mechanisms underlying the generation of each pain state. Such pain is difficult to treat and the treatment at present is inadequate. Corydalis yanhusuo is a traditional Chinese medicine with demonstrated analgesic efficacy in humans. The potential antihyperalgesic effect of its active component is L-tetrahydropalmatine (L-THP). L-THP has been used for the treatment of headache and other mild pain. However, little is known about its analgesic effect on chronic pain and its mechanism. Here, we report that L-THP exerts remarkable antihyperalgesic effects on neuropathic and inflammatory pain in animal models. Neuropathic hypersensitivity was induced by segmental spinal nerve ligation and inflammatory hypersensitivity was induced by an intraplantar injection of complete Freund's adjuvant. To determine the receptor mechanism underlying the antihyperalgesic actions of L-THP, we used SCH23390, an antagonist of a dopamine D1 receptor, in an attempt to block the antihyperalgesic effects of L-THP. We found that L-THP (1-4 mg/kg, i.p.) produced a dose-dependent antihyperalgesic effect in spinal nerve ligation and complete Freund's adjuvant models. The antihyperalgesic effects of L-THP were abolished by a dopamine D1 receptor antagonist SCH23390 (0.02 mg/kg). Furthermore, L-THP (4 mg/kg, i.p.) did not influence motor function. These findings suggest that L-THP may ameliorate mechanical hyperalgesia by enhancing dopamine D1 receptor-mediated dopaminergic transmission.

Background: Mitochondria play an important role in many cellular and physiologic functions. Mitochondria are dynamic organelles, and their fusion and fission regulate cellular signaling, development, and mitochondrial homeostasis. The most common complaint of human immunodeficiency virus (HIV)-sensory neuropathy is pain on the soles in patients with HIV, but the exact molecular mechanisms of HIV neuropathic pain are not clear. In the present study, we investigated the role of mitochondrial dynamin-related protein 1 (Drp1, a GTPase that mediates mitochondrial fission) in the perineural HIV coat glycoprotein gp120-induced neuropathic pain state., Methods: Neuropathic pain was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. Mechanical threshold was tested using von Frey filaments. The mechanical threshold response was assessed over time using the area under curves. Intrathecal administration of antisense oligodeoxynucleotide (ODN) against Drp1, mitochondrial division inhibitor-1 (mdivi-1), or phenyl-N-tert-butylnitrone (a reactive oxygen species scavenger) was given. The expression of spinal Drp1 was examined using western blots. The expression of mitochondrial superoxide in the spinal dorsal horn was examined using MitoSox imaging., Results: Intrathecal administration of either antisense ODN against Drp1 or mdivi-1 decreased mechanical allodynia (a sensation of pain evoked by nonpainful stimuli) in the gp120 model. Intrathecal ODN or mdivi-1 did not change basic mechanical threshold in sham surgery rats. Intrathecal Drp1 antisense ODN decreased the spinal expression of increased Drp1 protein induced by peripheral gp120 application. Intrathecal phenyl-N-tert-butylnitrone reduced mechanical allodynia. Furthermore, both intrathecal Drp1 antisense ODN and mdivi-1 reversed the upregulation of mitochondrial superoxide in the spinal dorsal horn in the gp120 neuropathic pain state., Conclusions: These data suggest that mitochondrial division plays a substantial role in the HIV gp120-related neuropathic pain state through mitochondrial reactive oxygen species and provides evidence for a novel approach to treating chronic pain in patients with HIV.

Background: There has recently been a substantial increase in the survival of prematurely born neonates and an increase of in utero surgeries. Noxious stimulation in the newborn alters the pain response to injury in adult life. Progesterone, an effective antihyperalgesic agent in the adult, is at high concentration in the pregnant mother. Therefore, we investigated the effects of early-life progesterone on postsurgical outcomes in adult rats., Methods: Female rat pups were administered progesterone or vehicle during the first 7 days postpartum (P1-P7). A second control group had no injections. Half of each of these groups received an incision of the hindpaw at P3 and the other half did not. At P60, all groups of these now adult rats received a second paw incision. Tactile sensitivity and thermal sensitivity were measured weekly at P14-P42 (period I), at P60 (just before the second incision), and every 2 days of P61-P70 (period II). At P67, rats were fixed by systemic paraformaldehyde perfusion and their spinal cords taken for staining and immunocytochemical analysis of activated p-p38 mitogen-activated protein kinase., Results: Rats with surgery at P3 had greater tactile and thermal hyperalgesia in period I than the nonoperated rats, a difference abolished by progesterone treatment. P3 incision also resulted in long-lasting tactile and thermal hyperalgesia after the P60 incision (period II), both of which were markedly smaller in degree and faster to resolve in rats receiving early progesterone. Even in rats that were not operated on in period I, neonatal progesterone lessened the tactile hyperalgesia in period II. More spinal cells showed p-p38 staining in vehicle-treated rats as a result of the early-life incision but not in those treated with progesterone., Conclusions: These findings suggest that endogenously high progesterone in utero may have a similarly protective action and that the development of nociceptive circuitry can be strongly influenced by neonatal progesterone.

Background: Duloxetine is an antidepressant effective for major depressive disorder and also the alleviation of pain for patients with diabetic peripheral neuropathy, chronic musculoskeletal pain, and fibromyalgia. How duloxetine works in pain relief remains unknown. In this study, we address whether duloxetine could act as an analgesic via systemic and local applications., Methods: Efficacies of bupivacaine and duloxetine applied subcutaneously at the incision site against acute postoperative pain were compared after rat skin incision. Contralateral and intraperitoneal injections were used to assess systemic efficacy of duloxetine. Local anesthetic actions were assayed through functional block of the rat sciatic nerve. Inhibition by duloxetine of neuronal Na channels was characterized in rat GH3 cells., Results: Our studies showed that subcutaneous duloxetine (2 mg) reduced hyperalgesia and allodynia for several days after skin incision, whereas subcutaneous bupivacaine (2 mg) did not. Contralaterally injected duloxetine (10 mg) had minimal effects on postoperative pain. Intraperitoneal duloxetine also reduced both allodynia and hyperalgesia, albeit at higher doses (10-20 mg). Duloxetine (2 mg) inhibited motor and nociceptive functions via sciatic nerve block for approximately 24 hours. It also reduced Na currents with 50% inhibitory concentrations of 30.4 ± 1.2 μM and 4.26 ± 0.19 μM (n = 8) for resting and fast-inactivated channels, respectively. Furthermore, duloxetine (10 μM) elicited additional use-dependent block of peak Na currents by approximately 70% when stimulated at 5 Hz., Conclusions: Our results demonstrate that duloxetine can act as a local anesthetic and an analgesic drug via both local and systemic applications. Because duloxetine inhibits neuronal Na currents with high potency, it may exert its antihyperalgesic effects through inhibition of the spontaneous nerve impulses that result from peripheral injury, encompassing its actions on multiple central nervous system and peripheral targets.

Background: Insulin therapy plays a critical role in managing type 1 diabetes mellitus, and exercise produces alterations in pain sensation. This experiment explored the effects of insulin therapy combined with treadmill training on diabetic neuropathic pain and on the expression of malondialdehyde (MDA) and cytokines., Methods: Rats were given 4 weeks of insulin (100 IU/kg) therapy and treadmill training (30-60 min/d of training at 20-25 m/min) each day beginning on day 3 after streptozotocin (65 mg/kg, IV) injection and continuing until day 27. Sensitivity to heat and mechanical stimuli and the expression of interleukin (IL)-10, IL-6, tumor necrosis factor-α, and MDA in the sciatic nerve were estimated., Results: We showed that 2 to 4 weeks of treadmill training, insulin treatment, or their combination increased both paw withdrawal thresholds and latencies compared with the same regimen in sedentary diabetic rats (all P < 0.0022). Treatment with insulin, but without treadmill training, had significant effects on glycemic control (P < 0.0001) and restored body weight (P < 0.0001) in the diabetic rats. The diabetic rats demonstrated the upregulation (all P < 0.009) of IL-6, MDA, and tumor necrosis factor-α in the sciatic nerve on days 14 and 28 after streptozotocin treatment, whereas in diabetic rats receiving insulin, treadmill training, or a combination (all P < 0.01), this upregulation was decreased. Insulin, treadmill training, or the combination increased IL-10 expression (all P < 0.0051) in all diabetic rats., Conclusions: Treadmill training combined with insulin therapy showed the best improvements in tactile allodynia and thermal hyperalgesia among our 3 treatment groups. The benefits of insulin intervention and treadmill training could be related to chronic inflammation (proinflammatory cytokines) and oxidative stress (MDA).

Damage on one side of the body can also result in pain on the contralateral unaffected side, called mirror-image pain (MIP). Currently, the mechanisms responsible for the development of MIP are unknown. In this study, we investigated the involvement of spinal microglia and interleukin-1β (IL-1β) in the development of MIP using a peripheral inflammatory pain model. After unilateral carrageenan injection, mechanical allodynia (MA) in both hind paws and the expression levels of spinal Iba-1, IL-1β, and GFAP were evaluated. Ipsilateral MA was induced beginning at 3 hours after carrageenan injection, whereas contralateral MA showed a delayed onset occurring 5 days after injection. A single intrathecal (i.t.) injection of minocycline, a tetracycline derivative that displays selective inhibition of microglial activation, or an interleukin-1 receptor antagonist (IL-1ra) on the day of carrageenan injection caused an early temporary induction of contralateral MA, whereas repeated i.t. treatment with these drugs from days 0 to 3 resulted in a long-lasting contralateral MA, which was evident in its advanced development. We further showed that IL-1β was localized to microglia and that minocycline inhibited the carrageenan-induced increases in spinal Iba-1 and IL-1β expression. Conversely, minocycline or IL-1ra pretreatment increased GFAP expression as compared with that of control rats. However, i.t. pretreatment with fluorocitrate, an astrocyte inhibitor, restored minocycline- or IL-1ra-induced contralateral MA. These results suggest that spinal IL-1β derived from activated microglia temporarily suppresses astrocyte activation, which can ultimately prevent the development of contralateral MA under inflammatory conditions. These findings imply that microglial IL-1β plays an important role in regulating the induction of inflammatory MIP.

Background: Postoperative pain is treated incompletely and ineffectively in many circumstances, and chronic postoperative pain causes suffering and diminishes productivity. The objective of this project is to determine whether a recently developed slow-release formulation of bupivacaine was effective in reducing the experimental chronic postoperative pain., Methods: In male Sprague-Dawley rats (250-300 g body weight), bupivacaine-releasing microspheres (MS-Bupi), containing 60 mg of bupivacaine base, were locally injected (MS-Bupi-L) 2 hours preoperatively into the subcutaneous compartment at the locus for experimental thoracotomy. Hypersensitivity to tactile stimulation was assessed by reductions in the threshold force required to induce a response to von Frey filaments (VFH) applied to the hairy back near the incision/retraction site. Pain behavior was assessed using a Qualitative Hyperalgesia Profile. Control groups included rats receiving the same dose of MS-Bupi but at a distant site on the back (MS-Bupi-D, testing for systemic drug actions) and rats receiving the same mass of microspheres with no drug (MS-Placebo) at the wound site. Rats were tested for 3 days before and 28 days (postoperative days [PODs]) after the procedure. Withdrawal threshold differences, which were the primary outcome measure, among all treatment groups were assessed by the Kruskal-Wallis test, after which pairwise comparisons were made by determining Wilcoxon-Mann-Whitney odds (WMWodds), with Bonferroni correction of the confidence intervals., Results: Microsphere bupivacaine released near the incision reduced the chronic tactile allodynia after thoracotomy. The threshold values during PODs 14 to 28 were different among the 3 treatment groups when examined on PODs 14, 16, 18, 23, 25, and 28 but not on POD21 (P = 0.0603). WMWodds showed that threshold of the MS-Bupi-L group differed from those of the MS-Bupi-D and the MS-Placebo groups for all the tested PODs, whereas the thresholds of the MS-Bupi-D group never differed from those of the MS-Placebo group. Area-under-curve analysis for threshold reductions below baseline, using WMWodds, also showed a reduction during the entire 28 PODs that was greater for the MS-Bupi-L group compared with the MS-Placebo or MS-Bupi-D group. The incidence of intense pain scores by the Qualitative Hyperalgesia Profile analysis was observed in 7 of 8 rats in the MS-Placebo group and in 5 of 8 rats in the MS-Bupi-L group., Conclusions: Local slow release of bupivacaine subcutaneously from the MS-Bupi formulation suppresses postoperative mechanical hypersensitivity for ≥4 weeks after experimental thoracotomy. Systemic bupivacaine from this treatment has no effect on this hypersensitivity.

In rodents, acute exposure to opioids results in transient antinociception followed by longer lasting hypersensitivity to tactile or thermal stimuli, a phenomenon termed opioid-induced hyperalgesia. This hypersensitivity can be blocked or reversed by intrathecally administered cyclooxygenase inhibitors, including ketorolac, suggesting a role for spinal prostaglandins. In surgical patients, the dose of intraoperative opioid, particularly the short-acting drug, remifentanil, is directly related to increased pain and opioid requirements for many hours postoperatively. In addition, experimentally induced tactile hypersensitivity in humans is exaggerated after cessation of remifentanil infusions. The degree of this experimental opioid-induced hyperalgesia is reduced by systemic treatment with cyclooxygenase inhibitors, and investigators have speculated that this reduction reflects the actions in the central nervous system, most likely in the spinal cord. To test this hypothesis, we measured cerebrospinal fluid prostaglandin E2 concentrations during and after remifentanil infusion in 30 volunteers. These volunteers received intrathecal ketorolac or saline in a random, blinded manner during intravenous remifentanil infusion after generation of hypersensitivity by topical capsaicin. Remifentanil reduced pain to noxious heat stimuli and reduced areas of capsaicin-induced hypersensitivity similarly in those receiving intrathecal ketorolac or saline. The primary outcome measure, area of capsaicin-induced hypersensitivity after stopping remifentanil, showed a similar increase in those receiving ketorolac as in those receiving saline. Cerebrospinal fluid prostaglandin E2 concentrations did not increase during postinfusion hyperalgesia compared with those during infusion, and they were not increased during infusion compared with those in historical controls. These data fail to support the hypothesis that acute opioid-induced hyperalgesia reflects spinal cyclooxygenase activation causing central sensitization.

Background: Many studies have confirmed that brief remifentanil exposure can enhance pain sensitivity. We previously reported that activation of glycogen synthase kinase-3β (GSK-3β) contributes to remifentanil-induced hyperalgesia via regulating N-methyl-D-aspartate receptor plasticity in the spinal dorsal horn. In this study, we demonstrated that GSK-3β inhibition prevented remifentanil-induced postoperative hyperalgesia via regulating α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor (AMPAR) expression and function in the spinal dorsal horn., Methods: Using a rat model of remifentanil-induced incision hyperalgesia, mechanical and thermal pain was tested 1 day before infusion and 2 hours, 6 hours, 1 day, 2 days, 3 days, 5 days, and 7 days after infusion. Western blot analysis was used to detect AMPAR subunit (GluR1 and GluR2) trafficking, AMPAR phosphorylation status, and GSK-3β activity in the spinal dorsal horn. Furthermore, whole-cell patch-clamp recording was used to analyze the effect of GSK-3β inhibition on AMPAR-induced current in the spinal dorsal horn., Results: Membrane AMPAR subunit GluR1 was upregulated in the spinal cord in remifentanil-induced postoperative hyperalgesia rats (275 ± 36.54 [mean ± SD] vs 100 ± 9.53, P = 0.0009). Selective GSK-3β inhibitors, LiCl and TDZD, treatment ameliorates remifentanil-induced postoperative hyperalgesia, and this was associated with the downregulated GluR1 subunit in the membrane fraction (254 ± 23.51 vs 119 ± 14.74, P = 0.0027; 254 ± 23.51 vs 124 ± 9.35, P = 0.0032). Moreover, remifentanil incubation increased the amplitude and the frequency of AMPAR-induced current in dorsal horn neurons (61.09 ± 9.34 pA vs 32.56 ± 6.44 pA, P = 0.0009; 118.32 ± 20.33 milliseconds vs 643.67 ± 43.29 milliseconds, P = 0.0002), which was prevented with the application of LiCl and TDZD, respectively. Remifentanil-induced postoperative pain induced an increase in pGluR1 Ser845 and Rab5, which was prevented with the application of LiCl and TDZD., Conclusions: These results indicate that amelioration of remifentanil-induced postoperative hyperalgesia by GSK-3β inhibition is attributed to downregulated AMPAR GluR1 expression in the membrane fraction and inhibition of AMPAR function via altering pGluR1 and Rab5 expression in the spinal dorsal horn.

Background: Human immunodeficiency virus (HIV)-associated sensory neuropathy is a common neurological complication of HIV infection affecting up to 30% of HIV-positive individuals. However, the exact neuropathological mechanisms remain unknown, which hinders our ability to develop effective treatments for HIV-related neuropathic pain (NP). In this study, we tested the hypothesis that inhibition of proinflammatory factors with overexpression of interleukin (IL)-10 reduces HIV-related NP in a rat model., Methods: NP was induced by the application of recombinant HIV-1 envelope protein gp120 into the sciatic nerve. The hindpaws of rats were inoculated with nonreplicating herpes simplex virus (HSV) vectors expressing anti-inflammatory cytokine IL-10 or control vector. Mechanical threshold was tested using von Frey filaments before and after treatments with the vectors. The mechanical threshold response was assessed over time using the area under curves. The expression of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 in both the lumbar spinal cord and the L4/5 dorsal root ganglia (DRG), was examined at 14 and 28 days after vector inoculation using Western blots., Results: We found that in the gp120-induced NP model, IL-10 overexpression mediated by the HSV vector resulted in a significant elevation of the mechanical threshold that was apparent on day 3 after vector inoculation compared with the control vector (P < 0.001). The antiallodynic effect of the single HSV vector inoculation expressing IL-10 lasted >28 days. The area under curve in the HSV vector expressing IL-10 was increased compared with that in the control vector (P < 0.0001). HSV vectors expressing IL-10 reversed the upregulation of phosphorylated p38 mitogen-activated kinase, tumor necrosis factor-α, stromal cell-derived factor-1α, and C-X-C chemokine receptor type 4 expression at 14 and/or 28 days in the DRG and/or the spinal dorsal horn., Conclusions: Our studies demonstrate that blocking the signaling of these proinflammatory molecules in the DRG and/or the spinal cord using the HSV vector expressing IL-10 is able to reduce HIV-related NP. These results provide new insights on the potential mechanisms of HIV-associated NP and a proof of concept for treating painful HIV sensory neuropathy with this type of gene therapy.

Background: N-methyl-D-aspartate receptor (NMDARs)-dependent central sensitization plays an important role in cancer pain. Binding of NMDAR subunit 2B (NR2B) by postsynaptic density protein-95 (PSD-95) can couple NMDAR activity to intracellular enzymes, such as neuronal nitric oxide synthase (nNOS), facilitate downstream signaling pathways, and modulate NMDAR stability, contributing to synaptic plasticity. In this study, we investigated whether perturbing the specific interaction between spinal NR2B-containing NMDAR and PSD-95, using a peptide-mimetic strategy, could attenuate bone cancer-related pain behaviors., Methods: Osteosarcoma cells were implanted into the intramedullary space of the right femurs of C3H/HeJ mice to induce progressive bone cancer-related pain behaviors. Western blotting was applied to examine the expression of spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95. We further investigated the effects of intrathecal injection of the mimetic peptide Myr-NR2B9c, which competitively disrupts the interaction between PSD-95 and NR2B, on nociceptive behaviors and on the upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95 associated with bone cancer pain in the spinal cord., Results: Inoculation of osteosarcoma cells induced progressive bone cancer pain and resulted in a significant upregulation of phospho-Tyr1472 NR2B, nNOS, and PSD-95. Intrathecal administration of Myr-NR2B9c attenuated bone cancer-evoked mechanical allodynia, thermal hyperalgesia, and reduced spinal phospho-Tyr1472 NR2B, nNOS, and PSD-95 expression., Conclusions: Intrathecal administration of Myr-NR2B9c reduced bone cancer pain. Internalization of spinal NR2B and dissociation NR2B-containing NMDARs activation from downstream nNOS signaling may contribute to the analgesic effects of Myr-NR2B9c. This approach may circumvent the negative consequences associated with blocking NMDARs, and may be a novel strategy for the treatment of bone cancer pain.

Objective: This study investigated the effects of written emotional disclosure on a model of chronic pain in healthy women with and without trauma history., Method: Participants were prescreened for their trauma history (N = 78) and randomized to a disclosure or a control writing condition. Pain testing occurred either 1 day or 1 month after disclosure. Capsaicin was applied to the forearm to evoke spontaneous burning pain at the application site and mechanical secondary hyperalgesia in the surrounding untreated skin., Results: As hypothesized, the effect of disclosure on the area and intensity of secondary hyperalgesia depended on trauma history and time of testing (F(1,69) ≥ 7.37, p = .008). Disclosure increased secondary hyperalgesia in participants with trauma history compared with those without trauma when testing occurred 1 day after writing (F(1,69) ≥ 5.27, p ≤ .025), whereas the opposite pattern was observed 1 month later (F(1,69) ≥ 4.88, p ≤ .031). Of the participants with trauma history in the disclosure condition, secondary hyperalgesia was reduced at 1 month compared with 1 day after writing (p = .001). Moreover, greater use of positive emotional words predicted reduced secondary hyperalgesia at 1 month (β = -0.71, p = .022). In contrast, disclosure had no effect on spontaneous pain., Conclusions: Disclosure modulates secondary hyperalgesia observed in women with trauma history, producing a short-term enhancement and a long-term reduction. This suggests that disclosure has a long-term protective effect that reduces sensitization of pain, which may explain the therapeutic effects of disclosure in patients with chronic pain.

Background: In the human immunodeficiency virus (HIV)-associated sensory neuropathy, neuropathic pain associated with the use of nucleoside reverse transcriptase inhibitors (NRTIs) in patients with HIV/acquired immunodeficiency syndrome is clinically common. While evidence demonstrates that neuropathic pain is influenced by neuroinflammatory events that include the proinflammatory molecules, tumor necrosis factor-α (TNF-α), stromal cell-derived factor 1-α (SDF1-α), and C-X-C chemokine receptor type 4 (CXCR4), the detailed mechanisms by which NRTIs contribute to the development of neuropathic pain are not known. In this study, we investigated the role of these proinflammatory molecules in the dorsal root ganglion (DRG) and the spinal dorsal horn in NRTIs-mediated neuropathic pain state., Methods: Neuropathic pain was induced by intraperitoneal administration of 2',3'-dideoxycytidine (ddC, one of the NRTIs). Mechanical threshold was tested using von Frey filament fibers. Nonreplicating herpes simplex virus (HSV) vectors expressing p55 TNF soluble receptor (p55TNFSR) were inoculated into hindpaw of rats. The expression of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG was examined using Western blots. Intrathecal CXCR4 antagonist was administered., Results: The present study demonstrated that (1) systemic ddC induced upregulation of TNF-α, SDF1-α, and CXCR4 in both the lumbar spinal cord and the L4/5 DRG; (2) p55TNFSR mediated by a nonreplicating HSV vector reversed mechanical allodynia induced by systemic ddC; (3) intrathecal administration of the CXCR4 antagonist AMD3100 increased mechanical threshold; and (4) HSV vector expressing p55TNFSR reversed upregulation of TNF-α, SDF1-α, and CXCR4 induced by ddC in the lumbar spinal dorsal horn and the DRG., Conclusions: Our studies demonstrate that TNF-α through the SDF1/CXCR4 system is involved in the NRTIs-related neuropathic pain state and that blocking the signaling of these proinflammatory molecules is able to reduce NRTIs-related neuropathic pain. These results provide a novel mechanism-based approach (gene therapy) to treating HIV-associated neuropathic pain.

The pathophysiology of the complex regional pain syndrome involves enhanced neurogenic inflammation mediated by neuropeptides. Neutral endopeptidase (neprilysin, NEP) is a key enzyme in neuropeptide catabolism. Our previous work revealed that NEP knock out (ko) mice develop more severe hypersensitivity to thermal and mechanical stimuli after chronic constriction injury (CCI) of the sciatic nerve than wild-type (wt) mice. Because treatment with glucocorticoids is effective in early complex regional pain syndrome, we investigated whether methylprednisolone (MP) reduces pain and sciatic nerve neuropeptide content in NEP ko and wt mice with nerve injury. After CCI, NEP ko mice developed more severe thermal and mechanical hypersensitivity and hind paw edema than wt mice, confirming previous findings. Hypersensitivity was prevented by MP treatment in NEP ko but not in wt mice. MP treatment had no effect on protein levels of calcitonin-gene related peptide, substance P, and bradykinin in sciatic nerves of NEP ko mice. Endothelin-1 (ET-1) levels were higher in naïve and nerve-injured NEP ko than in wt mice, without an effect of MP treatment. Gene expression of the ET-1 receptors ETAR and ETBR was not different between genotypes and was not altered after CCI, but was increased after additional MP treatment. The ETBR agonist IRL-1620 was analgesic in NEP ko mice after CCI, and the ETBR antagonist BQ-788 showed a trend to reduce the analgesic effect of MP. The results provide evidence that MP reduces CCI-induced hyperalgesia in NEP ko mice, and that this may be related to ET-1 via analgesic actions of ETBR., (Copyright © 2013 International Association for the Study of Pain. Published by Elsevier B.V. All rights reserved.)

Study Design: Animal experimental study with intervention., Objective: The aim of this study was to elucidate therapeutic effects of delayed granulocyte colony-stimulating factor treatment for mechanical allodynia induced by chronic constriction injury (CCI) of the sciatic nerve in rats., Summary of Background Data: Granulocyte colony-stimulating factor (G-CSF) is used clinically for patients with hematological disorders. Previous reports showed that immediate G-CSF attenuates neuropathic pain in CCI of the sciatic nerve. However, the acute treatment for neuropathic pain prior to accurate diagnosis is not realistic in clinical settings., Methods: Adult, female Sprague-Dawley rats were subjected to the CCI model. This model induces mechanical allodynia on the ipsilateral hind paw within the first week after the injury. One week after CCI, rats received intraperitoneal G-CSF (15.0 μg/kg) for 5 consecutive days. Mechanical allodynia was assessed using the von Frey hair test. Immunohistochemistry for phosphorylated p38 mitogen-activated kinase (p-p38MAPK) and OX-42 (a marker for activated microglia) on tissue slides from a subset of rats 2 weeks after surgery. Western blot analyses were carried out to determine protein expression level of p-p38MAPK and interleukin-1 β on spinal cord homogenates 2 weeks after CCI., Results: Results of the von Frey filament test showed that G-CSF significantly attenuates mechanical allodynia induced by the CCI model. Immunohistochemistry revealed that G-CSF reduced the number of p-p38MAPK-positive cells in the ipsilateral dorsal horn compared with that in the vehicle group rats. Immunofluorescent double staining revealed that p-p38MAPK-expressing cells in the spinal cord dorsal horn are mainly microglia. Western blot analysis indicated that G-CSF decreased the expression levels of both p-p38MAPK and interleukin-1 β in the ipsilateral dorsal horn compared with that in the vehicle group rats., Conclusion: The present results indicate a beneficial effect of delayed G-CSF treatment in an animal model of peripheral nerve injury-induced neuropathic pain., Level of Evidence: N/A.

Purpose of Review: The aim of the present review is to describe how regional anaesthesia might oppose neuronal changes that surgery and opioids cause in the central nervous system to block both pain sensitization and chronicization following surgery. This might help anaesthesiologists to better understand the impact of their practice on the development of postoperative chronic pain., Recent Findings: Even though there are more evidences from animals and clinical trials showing that regional anaesthesia might impact the acute pain/hyperalgesia and chronic postsurgical pain, the controversy on how and when to use regional anesthesia to avoid chronic pain persists. Animal studies brought only a very partial answer on what to do in our daily clinical practice. Clinical studies were performed in different types of surgery with various protocols so that a strong conclusion on whether or not using regional anesthesia might benefit the patient to decrease the risk of postoperative chronic pain remains unclear. Studies performed with neuraxial anaesthesia seem to bring better evidences than those with nerve blocks. Future studies will have to specifically evaluate acute hyperalgesia and postoperative chronic pain and not only the classical pain scores and analgesic consumption to bring us the answer we all need., Summary: Regional anaesthesia is able to reduce postoperative acute hyperalgesia and long-term chronic pain by decreasing pain sensitization induced by the surgery itself, and intraoperative use and opioid-induced hyperalgesia. Nevertheless, clinical studies on neuraxial anaesthesia and nerve blocks did not bring so far a strong conclusion to this question, and further better designed studies are necessary.

Study Design: Experimental animal study., Objective: This study investigated whether nitric oxide (NO) mediated protein nitration is involved in the pathogenesis of radiculopathy and whether the symptoms can be relieved by its suppression., Summary of Background Data: It has been reported that nitration of protein mediated by NO is involved in the degenerative neurological disorders, but its involvement is not clear in the radiculopathy., Methods: Two kinds of rat models of radiculopathy were used. Radiculopathy was induced either by ligation of spinal nerve roots or transplantation of autologous nucleus pulposus. In separate groups of rats, aminoguanidine, a potent nitric oxide synthetase inhibitor, was administered just before induction of radiculopathy, to suppress NO production and resultant nitration of protein. Sensation of the hind limb was evaluated by plantar stimulation test, and motor weakness was assessed by observation of gait pattern. Nitrotyrosine, product of protein nitration, was assayed quantitatively by Western immunoblotting., Results: Mechanical allodynia was observed in both compression and nucleus pulposus groups, but motor weakness was observed only in the compression group. Preoperative administration of aminoguanidine attenuated mechanical allodynia and motor weakness. Optical densities of nitrotyrosine bands increased significantly in radiculopathy groups, but they were lowered by administration of aminoguanidine., Conclusion: NO mediated protein nitration contributes to the development of both types of radiculopathies. Suppression of NO production can decrease protein nitration and relieve neural dysfunctions of radiculopathy., Level of Evidence: N/A.

Background: Acute postoperative pain causes physiological deficits and slows recovery. Reduction of such pain by local anesthetics that are delivered for several days postoperatively is a desirable clinical objective, which is approached by a new formulation and applied in animal studies reported here., Methods: We subcutaneously injected a new formulation of poly-lactic-co-glycolic acid polymer microspheres, which provides steady drug release for 96+ hours into rats at the dorsal region 2 hours before surgery. A single 1.2-cm-long skin incision was followed by blunt dissection of skin away from the underlying fascia, and closed by 2 sutures, followed by 14 days of testing. Microspheres containing 5, 10, 20, and 40 mg bupivacaine were injected locally 2 hours before surgery; bupivacaine-free microspheres were the vehicle control, and bupivacaine HCl solution (0.5%), the positive control. Mechanical sensitivity was determined by the frequency of local muscle contractions to repeated pokes with nylon monofilaments (von Frey hairs) exerting 4 and 15 g forces, testing, respectively, allodynia and hyperalgesia, and by pinprick., Results: Injection of bupivacaine microspheres (40 mg drug) into intact skin reduced responses to 15 g von Frey hairs for 6 hours and to pinprick for 36 hours. Respective reductions from bupivacaine HCl lasted for 3 and 2 hours. Skin incision and dissection alone caused mechanical allodynia and hyperalgesia for 14 days. Microspheres containing 20 or 40 mg bupivacaine suppressed postoperative hypersensitivity for up to 3 days, reduced integrated allodynia (area under curve of response versus time) over postoperative days 1 to 5 by 51% ± 20% (mean ± SE) and 78% ± 12%, and reduced integrated hyperalgesia by 55% ± 13% and 64% ± 11%, for the respective doses. Five and ten milligrams bupivacaine in microspheres and the 0.5% bupivacaine solution were ineffective in reducing postoperative hypersensitivity, as were 40 mg bupivacaine microspheres injected contralateral to the incision., Conclusions: Significant suppression of postoperative pain by the slow-release bupivacaine preparation outlasts its anesthetic action on intact skin. These findings demonstrate preventive analgesia and indicate the importance of acute processes in the development of chronic postoperative pain.

Objectives: There is no study on the role of prophylactic therapy on allodynia in patients with migraine. We report the predictors of allodynia in migraine and the effect of divalproate or amitriptyline in alleviating allodynia., Methods: Four hundred forty-eight consecutive patients with migraine diagnosed as per International Headache Society criteria were prospectively included. The presence of allodynia, its type and severity, and details of headache were enquired. Two hundred twenty-seven migraineurs were randomly allocated to amitriptyline (25 to 50 mg/d) or divalproate (500 to 750 mg/d). The improvement in allodynia and headache severity was recorded at 3 and 6 months. The side effects of the drugs were noted., Results: The median age of the patients was 32 years (range, 10 to 62 y) and 77.6% were females. 71.4% patients had allodynia; static mechanical in 90%, dynamic in 89.1%, and thermal in 17%. The allodynia was related to the duration of illness, frequency, severity of migraine, and female gender. Both divalproate and amitriptyline significantly reduced the frequency and severity of allodynia at 3 and 6 months compared with baseline though there was no group difference. The composite side effects were similar but valproate was discontinued in 5 patients because of polycystic ovary., Conclusions: 71.4% migraineurs had allodynia that was related to the duration, severity, frequency of migraine, and female gender. Divalproate and amitriptyline were equally effective in relieving allodynia.

Treatment of severe pain by morphine, the gold-standard opioid and a potent drug in our arsenal of analgesic medications, is limited by the eventual development of hyperalgesia and analgesic tolerance. We recently reported that systemic administration of a peroxynitrite (PN) decomposition catalyst (PNDC) or superoxide dismutase mimetic attenuates morphine hyperalgesia and antinociceptive tolerance and reduces PN-mediated mitochondrial nitroxidative stress in the spinal cord. These results suggest the potential involvement of spinal PN signaling in this setting; which was examined in the present study. PN removal with intrathecal delivery of manganese porphyrin-based dual-activity superoxide/PNDCs, MnTE-2-PyP(5+) and the more lipophilic MnTnHex-2-PyP(5+), blocked hyperalgesia and antinociceptive tolerance in rats. Noteworthy is that intrathecal MnTnHex-2-PyP(5+) prevented nitration and inactivation of mitochondrial manganese superoxide dismutase. Mitochondrial manganese superoxide dismutase inactivation enhances the superoxide-to-PN pathway by preventing the dismutation of superoxide to hydrogen peroxide, thus providing an important enzymatic source for PN formation. Additionally, intrathecal MnTnHex-2-PyP(5+) attenuated neuroimmune activation by preventing the activation of nuclear factor kappa B, extracellular-signal-regulated kinase and p38 mitogen activated protein kinases, and the enhanced levels of proinflammatory cytokines, interleukin (IL)-1β and IL-6, while increasing anti-inflammatory cytokines, IL-4 and IL-10. The role of PN was further confirmed using intrathecal or oral delivery of the superoxide-sparing PNDC, SRI-110. These results suggest that mitochondrial-derived PN triggers the activation of several biochemical pathways engaged in the development of neuroinflammation in the spinal cord that are critical to morphine hyperalgesia and tolerance, further supporting the potential of targeting PN as an adjunct to opiates to maintain pain relief., (Copyright © 2013. Published by Elsevier B.V.)

Study Design: We measured the response of the behavior and spinal glial activation to anti-nerve growth factor receptor (p75 neurotrophin receptor [p75NTR]) antibodies in the rat brachial plexus avulsion (BPA) model., Objective: The aim of this study was to investigate the effect of anti-p75NTR antibodies on nociceptive behavior and activation of spinal microglia in the rat BPA model., Summary of Background Data: Tanezumab (anti-nerve growth factor antibody) treatment is associated with pain reduction and improvement in function, but with several complications., Methods: Thirty male Wistar rats were used. In the BPA group, the C8-T1 roots were avulsed from the spinal cord with forceps at the lower trunk level and 10 μL of saline was applied locally (n = 10). In the anti-p75NTR group, the C8-T1 roots were avulsed and 10 μL of anti-p75NTR antibody was applied locally (n = 10). In a sham-operated group, the lower trunk was simply exposed (n = 10). Mechanical hyperalgesia and pain-induced walking patterns were measured using von Frey filaments (Stoelting, Wood Dale, IL) and the CatWalk gait analysis (Noldus Information Technology, the Netherlands) system every third day for 3 weeks. Activation of astrocytes and microglia was immunohistochemically examined in the spinal cord using anti-glial fibrillary acidic protein (GFAP) and anti-Iba1 antibodies both 7 and 21 days after surgery., Results: Animals in the BPA group displayed significant mechanical hyperalgesia that continued through day 21 compared with animals in the sham-operated group, and mechanical hyperalgesia in the anti-p75NTR group was significantly improved 6 days after the operation. Regarding pain-induced gait analysis via CatWalk, animals in the BPA group displayed a significantly greater pain-like gait pattern than the p75 group for up to 3 weeks. Levels of GFAP-immunoreactive astrocytes and Iba1-immunoreactive microglia in the anti-p75NTR group were significantly reduced compared with the BPA group., Conclusion: Our results suggest that p75NTR contributes to neuropathic pain associated with BPA, and that inhibition of p75NTR reduces neuropathic pain., Level of Evidence: N/A.

Background: Chemotherapy-induced peripheral neuropathy is a common, dose-limiting side effect of cancer chemotherapeutic drugs. Hyperalgesia is a common component of neuropathic pain. Ginkgo biloba extract (GBE) is an oriental herbal medicine that has various pharmacological actions. In this study, we evaluated the effects of oral GBE on hyperalgesia in a rat model of vincristine-induced neuropathy., Methods: Male Sprague-Dawley rats (200-250 g) were injected intraperitoneally with vincristine or saline (0.1 mg/kg/d) using a 5-day-on, 2-day-off schedule over 12 days. All the behavioral tests for mechanical, cold, and heat hyperalgesia were conducted before the daily injection during the course of vincristine treatment. Rats that developed hyperalgesia 14 days after vincristine injection were randomly assigned into 4 groups. Distilled water and GBE (50, 100, and 150 mg/kg) were administered, respectively, to the individual groups. We examined the hyperalgesia at preadministration and at 15, 30, 60, 90, 120, 150, and 180 minutes after oral drug administration., Results: Saline injection did not have any significant effect on mechanical, cold, and heat hyperalgesia. Vincristine injection produced mechanical and cold hyperalgesia. For the GBE groups, the paw withdrawal threshold to mechanical stimuli was significantly increased and withdrawal frequency to cold stimuli was significantly reduced versus the control group dose-dependently (P < 0.05)., Conclusions: This study demonstrates that oral administration of GBE is associated with a dose-dependent antihyperalgesic effect on mechanical and cold stimuli in a rat model of vincristine-induced neuropathy.

Study Design: Spine deformity and pain-related behavior after laminectomy with and without spine stabilization were investigated., Objective: We tested hypothesis that spine stabilization after extensive laminectomy can prevent spine deformation and consequent pain-related behavior., Summary of Background Data: Various ablative procedures requiring laminectomy have been tested for prevention or reversal of pain-related behavior in studies using experimental animals. However, there is no precise description indicating how laminectomy should be performed. Lack of standardized surgical techniques makes it difficult to achieve uniformity of result reporting and to compare results of different research groups meaningfully., Methods: To test our hypothesis, extensive laminectomy with and without spine stabilization was performed in Sprague-Dawley rats. U-shaped surgical wire was used for stabilization of the spine. A validated test of mechanical hyperalgesia was used to test the development of neuropathic pain behavior after surgery. Deformity of the spine was evaluated by calculating deviation from the central axis on radiographs obtained in anteroposterior projection., Results: Surgical stabilization of the spine after laminectomy prevented development of spinal deformity. Laminectomy without stabilization induced hyperalgesia on the 8th and 15th days after surgery. Group with stabilized spine exhibited significant reduction in pain-related behavior on the 8th and 15th postoperative days compared with the group without stabilization., Conclusion: Surgical stabilization of the spine after laminectomy prevented development of spinal deformity and pain-related behavior. Our results suggest that spine stabilization procedure should be used in all experimental pain models in which laminectomy is performed.

Objectives: Breast cancer surgery is associated with a high incidence of persistent postsurgical pain (PPSP). The aim of this study was to evaluate the impact of intravenous (IV) lidocaine on acute and PPSP, analgesic requirements, and sensation abnormalities in patients undergoing surgery for breast cancer., Methods: Thirty-six patients participated in this randomized, double-blinded study. Before induction of general anesthesia, patients received a bolus of intravenous lidocaine 1.5 mg/kg followed by a continuous infusion of lidocaine 1.5 mg/kgh (lidocaine group) or an equal volume of saline (control group). The infusion was stopped 1 hour after the skin closure. Pain scores and analgesic consumption were recorded at 2, 4, 24 hours, and then daily for 1 week postoperatively. Three months later, patients were assessed for PPSP and secondary hyperalgesia., Results: Two (11.8%) patients in the lidocaine group and 9 (47.4%) patients in the control group reported PPSP at 3 months follow-up (P=0.031). McGill Pain Questionnaire revealed greater present pain intensity-visual analog scale in the control group (14.6 ± 22.5 vs. 2.6 ± 7.5; P=0.025). Secondary hyperalgesia (area of hyperalgesia/length of surgical incision) was significantly less in the lidocaine group compared with control group (0.2 ± 0.8 vs. 3.2 ± 4.5 cm; P=0.002). The 2 groups were similar in terms of analgesic consumption during the early postoperative period., Discussion: Intravenous perioperative lidocaine decreases the incidence and severity of PPSP after breast cancer surgery. Prevention of the induction of central hyperalgesia is a potential mechanism.

Purpose of Review: To summarize the relevant publications during the last 12 months supporting that diet can influence gas-related symptoms in the absence of a malabsorption state., Recent Findings: Gas symptoms during carbohydrate fermentation: a diet incorporating beans is well tolerated by a majority of individuals involved in a program of heart disease biomarkers. By contrast, in patients with irritable bowel syndrome, a diet avoiding fermentable carbohydrates improved gas-related abdominal symptoms. The rate of fermentation determines the production of abdominal symptoms, and many slowly fermentable fibers have a rapid fermentation profile that can generate abdominal symptoms. Modulation of visceral sensitivity: diet can influence gas symptoms by increasing the tolerability of the intestine to gas. Capsaicin decreases visceral hyperalgesia and improved bloating in patients with irritable bowel syndrome. Changes in gas-producing bacteria: different strains of Lactobacillus have antimicrobial properties against gas-forming coliforms. New clinical studies show beneficial effects of prebiotics and probiotics on abdominal bloating., Summary: Actual data suggest that diet could improve gas-related abdominal symptoms acting on several mechanisms: gas production, visceral hypersensitivity and modulation of gas-producing enteric bacteria.

Background: Myrsinoic acid B (MAB) is a diprenylated benzoic acid widely found in the vegetal kingdom. Recent studies demonstrate that MAB has important antinociceptive effects in models of chemically or thermally induced nociception in mice., Methods: In the present study we evaluated the effect of MAB in different models of inflammatory and neuropathic hypersensitivity in mice., Results: This study demonstrates that the pretreatment with MAB, given orally (8.4 to 83.8 μmol/kg), inhibited carrageenan- and complete Freund adjuvant-induced mechanical hypersensitivity. When administered after the induction of hypersensitivity, MAB also reduced the mechanical hypersensitivity in the ipsilateral and in the contralateral hindpaws of mice injected with complete Freund adjuvant, interfering with a signaling cascade already established. MAB reversed the hypersensitivity (mechanical and thermal) of operated animals, with similar results to those observed with gabapentin. MAB activity was evident when administered either systemically (PO or IV) or intrathecally, suggesting interference in the central pathways of pain control. Furthermore, MAB seems to present an antiinflammatory effect evidenced by the interference in both the neutrophil migration and in the increase of interleukin-1β levels after carrageenan injection. Of note, MAB treatment did not interfere with mechanical or thermal sensitivity in healthy mice, a frequent characteristic of commonly used analgesics, such as morphine or gabapentin. Side effects including interference in locomotor activity, motor performance, and body temperature in animals treated with MAB were absent., Conclusions: MAB reduced mechanical and thermal hypersensitivity in mice submitted to models of inflammatory and neuropathic pain, showing excellent potential for treating persistent pain in humans.

Background: Tolerance to remifentanil during sevoflurane anesthesia may blunt the ability of this drug to reduce anesthetic requirements. Gabapentin has been shown to be effective in reducing postoperative narcotic usage, a reduction that may be associated with a reduction in opioid-induced tolerance and hyperalgesia. We sought to determine whether gabapentin might prevent the observed acute opioid tolerance (AOT) produced by remifentanil in sevoflurane minimum alveolar concentration (MAC)., Methods: Wistar rats were anesthetized with sevoflurane and the effects of gabapentin alone on sevoflurane MAC were determined at doses of 150 and 300 mg · kg(-1). In a second experiment, gabapentin 300 mg · kg(-1) was administered before remifentanil (120 and 240 μg · kg(-1) · h(-1)). The MAC was determined before gabapentin administration and 3 more times at 1.5-hour intervals after drug administration to assess AOT. MAC was determined from intratracheal gas samples using a sidestream gas analyzer; tail clamping was used as a supramaximal stimulus. Statistical analysis was performed with the 1-way analysis of variance test., Results: Remifentanil reduced MAC (2.5 ± 0.2%) by 16% ± 5% and 36% ± 6% (120 and 240 μg · kg(-1) · h(-1), respectively, P < 0.01) with a further reduction produced by coadministration with gabapentin 300 mg · kg(-1) to 39% ± 12% and 62% ± 14%, respectively (P < 0.01 versus remifentanil alone). Gabapentin given alone at 150 and 300 mg · kg(-1) reduced MAC by 26% (both doses, P < 0.01). AOT was observed with remifentanil and characterized by a lower degree of MAC reduction, approximately 1.5 hours later (P < 0.05). However, when remifentanil was administered with gabapentin, the AOT to remifentanil was not observed (P > 0.05)., Conclusions: Gabapentin reduced the sevoflurane MAC and enhanced the MAC reduction produced by remifentanil. This enhancement may limit AOT in rats.

Background: Systemic α2 agonists are believed to reduce pain and opioid requirements after surgery, thus decreasing the incidence of opioid-related adverse effects, including hyperalgesia., Methods: The authors searched for randomized placebo-controlled trials testing systemic α2 agonists administrated in surgical patients and reporting on postoperative cumulative opioid consumption and/or pain intensity. Meta-analyses were performed when data from 5 or more trials and/or 100 or more patients could be combined., Results: Thirty studies (1,792 patients, 933 received clonidine or dexmedetomidine) were included. There was evidence of postoperative morphine-sparing at 24 h; the weighted mean difference was -4.1 mg (95% confidence interval, -6.0 to -2.2) with clonidine and -14.5 mg (-22.1 to -6.8) with dexmedetomidine. There was also evidence of a decrease in pain intensity at 24 h; the weighted mean difference was -0.7 cm (-1.2 to -0.1) on a 10-cm visual analog scale with clonidine and -0.6 cm (-0.9 to -0.2) with dexmedetomidine. The incidence of early nausea was decreased with both (number needed to treat, approximately nine). Clonidine increased the risk of intraoperative (number needed to harm, approximately nine) and postoperative hypotension (number needed to harm, 20). Dexmedetomidine increased the risk of postoperative bradycardia (number needed to harm, three). Recovery times were not prolonged. No trial reported on chronic pain or hyperalgesia., Conclusions: Perioperative systemic α2 agonists decrease postoperative opioid consumption, pain intensity, and nausea. Recovery times are not prolonged. Common adverse effects are bradycardia and arterial hypotension. The impact of α2 agonists on chronic pain or hyperalgesia remains unclear because valid data are lacking.

Background: The underlying mechanism of exercise on neuropathic pain is not well understood. We investigated whether physical exercise regulates the functional recovery and heat shock protein 72 (Hsp72), tumor necrosis factor-α (TNF-α), and interlukin-1β (IL-1β) expression after chronic constriction injury (CCI) of the sciatic nerve., Methods: Male Sprague-Dawley rats were divided into 7 groups: control, sham operated (SO), SO with swimming or treadmill exercise (SOSE or SOTE), CCI, CCI with swimming or treadmill exercise (CCISE or CCITE). We recorded body weight, thermal withdrawal latency, and mechanical withdrawal threshold as well as Hsp72, TNF-α, and IL-1β expression in sciatic nerve., Results: The body weights in the control and SO groups were heavier than those in the SOSE, SOTE, CCI, CCISE, and CCITE groups. CCI rats with swimming or treadmill exercise showed significant increase in thermal withdrawal latency and mechanical withdrawal threshold when compared with CCI rats without exercise on day 21 after CCI. Both CCISE and CCITE groups demonstrated greater Hsp72 expression and lower TNF-α or IL-1β level than did the CCI group in sciatic nerve on day 21 after CCI., Conclusions: These results suggest that progressive exercise training decreases peripheral neuropathic pain as well as TNF-α and IL-1β overproduction and increases HSP72 expression after CCI of the sciatic nerve.

Background: The administration of nonsteroidal anti-inflammatory drugs (NSAIDs) is the most common nonopioid analgesic currently used for postoperative pain management. We tested the sustained analgesic effect of ketoprofen emanating from a biodegradable gelatin hydrogel in a rat model of postoperative pain., Methods: A sheet of analgesic-infiltrated hydrogel was inserted below the plantaris muscle at the end of surgery. Mechanical thresholds were measured by use of von Frey filaments before and 2 weeks after the operation. The effect of ketoprofen on the postoperative pain was also assessed immunohistochemically by assessing microglial activation in the spinal cord with anti-OX-42 and phosphorylated p38 mitogen-activated protein kinase antibodies., Results: Implantation of ketoprofen-infiltrated gelatin hydrogel exerted a sustained analgesic effect for 1 week after the operation. Preemptive analgesia with zaltoprofen, another NSAID, produced an additive analgesic effect in conjunction with the ketoprofen-infiltrated hydrogel. Microglial activation was attenuated by the treatment with ketoprofen-infiltrated hydrogel on day 3 after the incision., Conclusions: These results demonstrate that ketoprofen was effective in reducing mechanical hypersensitivity for 1 week in a rat model of postoperative pain and that the implantation of NSAID-infiltrated gelatin hydrogel may serve as a useful analgesic method for the long-term relief of patients after surgery.